Human immunodeficiency virus type 1 (HIV-1) leads to the contraction of acquired immune deficiency disease (AIDS). The number of cases of HIV continues to rise, and currently over twenty-five million individuals worldwide suffer from the virus. Presently, long-term suppression of viral replication with antiretroviral drugs is the only option for treating HIV-1 infection. Indeed, the U.S. Food and Drug Administration has approved twenty-five drugs over six different inhibitor classes, which have been shown to greatly increase patient survival and quality of life. However, additional therapies are still required due to a number of issues including, but not limited to undesirable drug-drug interactions; drug-food interactions; non-adherence to therapy; drug resistance due to mutation of the enzyme target; and inflammation related to the immunologic damage caused by the HIV infection.
Currently, almost all HIV positive patients are treated with therapeutic regimens of antiretroviral drug combinations termed, highly active antiretroviral therapy (“HAART”).
However, HAART therapies are often complex because a combination of different drugs must be administered often daily to the patient to avoid the rapid emergence of drug-resistant HIV-1 variants. Despite the positive impact of HAART on patient survival, drug resistance can still occur and the survival and quality of life are not normalized as compared to uninfected persons [Lohse Ann Intern Med 2007 146; 87-95]. Indeed, the incidence of several non-AIDS morbidities and mortalities, such as cardiovascular disease, frailty, and neurocognitive impairment, are increased in HAART-suppressed, HIV-infected subjects [Deeks Annu Rev Med 2011; 62:141-155]. This increased incidence of non-AIDS morbidity/mortality occurs in the context of, and is potentially caused by, elevated systemic inflammation related to the immunologic damage caused by HIV infection [Hunt J Infect Dis 2014][Byakagwa J Infect Dis 2014][Tenorio J Infect Dis 2014].
Modern antiretroviral therapy (ART) has the ability to effectively suppress HIV replication and improve health outcomes for HIV-infected persons, but is believed to not be capable of completely eliminating HIV viral reservoirs within the individual. HIV genomes can remain latent within mostly immune cells in the infected individual and may reactivate at any time, such that after interruption of ART, virus replication typically resumes within weeks. In a handful of individuals, the size of this viral reservoir has been significantly reduced and upon cessation of ART, the rebound of viral replication has been delayed [Henrich T J J Infect Dis 2013][Henrich T J Ann Intern Med 2014]. In one case, the viral reservoir was eliminated during treatment of leukemia and no viral rebound was observed during several years of followup [Hutter G N Engl J Med 2009]. These examples suggest the concept that reduction or elimination of the viral reservoir may be possible and can lead to viral remission or cure. As such, ways have been pursued to eliminate the viral reservoir, by direct molecular means, including excision of viral genomes with CRISPR/Cas9 systems, or to induce reactivation of the latent reservoir during ART so that the latent cells are eliminated. Induction of the latent reservoir typically results in either direct death of the latently infected cell or killing of the induced cell by the immune system after the virus is made visible. As this is performed during ART, viral genomes produced are believed to not result in the infection of new cells and the size of the reservoir may decay.
Reactivation of latent HIV is believed to be achieved by several means, typically by broad and potent mechanisms of cellular activation. These reactivators can be specific to certain cell types, such as anti-CD3/anti-CD28 antibodies that will specifically target T cells, or can be non-specific, such as protein kinase C (PKC) agonists that can activate many cell types. PKC agonists have been described as effective at reactivating latent HIV. Several PKC agonists derived from plants and sponges have been described, including phorbol esters, bryostatin, englerin A, and ingenol.
Ingenol is a diterpenoid compound isolated from plant material derived from representatives of the of Euphorbia genus (e.g., sap or seeds of E. peplus, dried roots of E. kansui or E. pekinensis). E. peplus sap containing ingenols and other diterpenoids is a traditional medicine for use in skin diseases, including skin cancer, hence the nickname cancer weed. Similarly, E. kansui or E. pekinensis root are used in traditional Chinese medicine to treat malignancies such as leukemia, purging fluids, or inducing diarrhea. While ingenol is not the only active agent in Euphorbia extracts, it is believed to be among the more potent. A derivative of ingenol, ingenol mebutate, is licensed for clinical use in the USA under the trade name Picato® for the treatment of actinic keratosis.
WO 2012/085189, WO 2012/83954 and WO 2012/083953 describe derivates of 3-acyl-ingenol, 3-O-acyl-ingenol, as well as 3-O-carbamoyl-ingenol, which may be useful for the treatment of conditions which are affected by induction of cell death by cytotoxicity or induction of apoptosis and/or by an immunostimulatory effect.
WO 2013/126980 describes the use of certain ingenol derivatives as HIV reactivators of latent HIV virus in viral reservoirs.
WO 2014/001215 describes derivatives of 3-O-heteroaryl-ingenol useful for the treatment of conditions which are affected by induction of cell death by cytotoxicity or induction of apoptosis and/or by an immunostimulatory effect.
Notwithstanding the above, there remains a need for compounds which may possess a desirable combination of potency, limited cytotoxicity, and chemical properties for development as a therapy for HIV.